Obesity, glucose intolerance, hyperinsulinemia and insulin resistance are attributes of the genetically obese (ob/ob) mouse which make it particularly suitable as a model for human obesity and noninsulin-dependent diabetes. Such mice develop excess lipid stores while maintaining reduced growth of muscle and bone. Food restriction does not correct the obesity, but leads to continued storage of fat at the expense of lean body tissue. Interventions which increase insulin sensitivity (adrenalectomy and oxtetracycline treatment) reduce fat accretion and enhance growth of muscle and bone. Whether the improvement in insulin sensitivity is directly responsible for the amelioration of obesity is not known. One hypothesis is that insulin-induced increases in sympathetic nervous system activity and thermogenesis limit fat deposition, while anabolic effects of insulin on muscle and/or bone lead to enhanced growth of these tissues. The objective of this proposal is to enhance insulin sensitivity in the genetically obese (ob/ob) mouse by chronic administration of a sulfonylurea (glipizide or glyburide) in order to test the following hypotheses: 1) Treatment of ob/ob mice with sulfonylurea will be associated with reduced deposition of body fat and enhanced growth of muscle and bone; 2) Treatment of ob/ob mice with sulfonylurea will be associated with increased sympathetic nervous system activity; 3) Treatment of ob/ob mice with sulfonylurea will be associated with enhanced thermogenesis; 4) A high-fat diet, which reduces insulin sensitivity, will attenuate the effects of the sulfonylurea on the parameters noted above. Methods to be used include direct calorimetry and measurement of body fat, protein and energy content, 3H norepinephrine turnover, and brown adipose tissue mitochondrial GDP binding capacity. In addition, the effects of sulfonylurea on insulin sensitivity and glucose metabolism in specific tissues (muscle, brown adipose tissue, white adipose tissue and liver) of the ob/ob mouse will be delineated (measuring 2DG uptake, glucose oxidation, or incorporation of radiolabelled precursors into lipids or glycogen). If the above hypotheses are supported, these studies will provide additional evidence that insulin influences sympathetic nervous system activity and thermogenesis. Insulin-induced stimulation of these systems may affect energy balance by limiting fat storage (preventing the development of obesity) while promoting growth of lean body tissues (anabolic effects of insulin). Thus, the results of the proposed studies will extend our understanding of the role of insulin and diet in the pathogenesis of obesity.